Allogeneic hematopoietic stem cell transplantation (HSCT) is currently used for the treatment of a variety hematologic malignancies. Recently, there has been renewed interest in HSCT for solid cancers as well as solid organ transplantation and autoimmunity. However, the occurrence of graft-versus-host disease (GVHD), in both acute, and with increasing prevalence, chronic forms significantly limits the use and efficacy of this approach. Both forms of GVHD are driven by donor T cells and cytokines. While chronic GVHD has been emerging more and more in HSCT, there have been little preclinical studies assessing its control and concurrent effects on beneficial graft-versus-tumor (GVT) effects. We and others have shown that cytokines such as interferon-gamma (IFN?) and TNF1 play pivotal and dual roles in GVH/GVT responses. Further, molecular targeting of GVHD via proteasome or NFkB inhibition represents a novel means not only modulate GVHD but also promote GVT but mechanisms of action as well as effects in chronic GVHD remain not known. To build on our published and preliminary data we propose 3 Specific Aims to dissect both efficacy and mechanism of these two approaches - cytokine manipulation and molecular targeting. Specific Aim 1 will seek to dissect the roles of the IFN?/TNFa/IL-17 cytokine pathways in acute GVHD models through modulation by clinically translatable approaches by either by siRNA or antibody blockade. We will then combine with molecular targeting approaches to these models in an attempt to further control GVHD pathobiology using the proteasome inhibitor, bortezomib and a novel NFkB inhibitor. Specific Aim 2 will then determine the role of these cytokines in chronic GVHD models looking at skin and lung pathology and assess the efficacy of molecular targeting in not only prevention but also treatment of active disease. Specific Aim 3 will then use both solid and hematologic cancer models and assess the efficacy of these approaches on the prevention/control of GVHD and potential promotion of GVT. This proposal should not shed valuable insights on both acute and chronic GVHD but also allows for preclinical assessment of translatable approaches in their control as well as assessment in orthotopic cancer models.